A challenge in the conduct of clinical trials of therapies to prevent or delay the onset of type 1 diabetes is the large numbers of subjects needed to be tested over many years. The four completed fully powered trials aimed to prevent type 1 diabetes took 6-12 years to complete and involved screening more than 100,000 subjects. The enormity of such efforts effectively limits the number of therapies that can be evaluated. Strategies to address this challenge include improved risk stratification and the use of clinically and biologically relevant surrogate endpoints prior to the development of type 1 diabetes. Because therapies are designed with the intent to delay or halt progressive beta cell dysfunction and destruction, measures of beta cell function are expected to be useful in both aspects. As further discussed below, abnormal responses to intravenous (IV) or oral glucose have been successfully used along with autoantibody status for risk stratification and thus entry criteria for clinical trials to prevent type 1 diabetes. Yet, while these measures are predictive o disease, there are many individuals with markedly low insulin secretion to IV glucose who do not progress to type 1 diabetes. Moreover, there is surprisingly little change in c-peptide response to oral glucose in the years prior to type 1 diabetes onset. Since type 1 diabetes results from beta cell destruction, the inability of these measures to robustly track with disease progression implies that the measures used are an inadequate reflection of beta cell function. The aim of this study is to evaluate another measure of beta cell function, acute maximal insulin secretion (AIRmax), in individuals at risk for type 1 diabetes. AIRmax is a dynamic test that measures the acute insulin response to arginine in the presence of marked hyperglycemia. It is considered to reflect beta cell secretory capacity. The hypothesis is that AIRmax is a more sensitive measure of beta cell function than currently used tests and that its reproducibility and tolerability make t a suitable measure for risk stratification and as a biologically and clinically relevant endpoint in clinical trials to alter disease progression. If true, then initial clinical trials to determine th effect of therapies on disease progression in at risk individuals could be conducted using surrogate metabolic endpoints with fewer subjects and for shorter periods of time, thus allowing selection of therapies for subsequent definitive studies and facilitating translation of novel agents into clinical use. PUBLIC HEALTH RELEVANCE: Type 1 diabetes mellitus (T1DM) is an immune-mediated disease of children and adults in which insulin- producing beta cells are completely or near completely destroyed, resulting in life-long dependence on exogenous insulin. Despite improved treatments, individuals with type 1 diabetes still face significant morbidity and early mortality; thus, prevention of the onset of the disease would represent a significant advancement. Validation of surrogate metabolic biomarkers as described in this proposal will facilitate testing of novel therapies to prevent the disease.